The effect of erythromycin on the pharmacokinetics of rosuvastatin.

RATIONALE OBJECTIVE: To examine in vivo the effect of erythromycin on the pharmacokinetics of rosuvastatin [an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase]. Erythromycin is a potent inhibitor of CYP3A4 that markedly increases circulating levels of some other HMG-CoA reductase inhibitors. METHODS: In this randomised, double-blind, two-way cross-over, placebo-controlled trial 14 healthy volunteers were given 500 mg erythromycin or placebo four times daily for 7 days. A single dose of 80 mg rosuvastatin was co-administered on day 4 of dosing. Plasma concentrations of rosuvastatin and active and total HMG-CoA reductase inhibitors were measured up to 96 h after dosing. RESULTS: Eleven volunteers had data available from both dosing periods. There was no increase in rosuvastatin plasma exposure following co-administration with erythromycin compared to placebo. In fact, following co-administration with erythromycin, rosuvastatin geometric least square mean AUC((0-t)) and C(max) were 20% and 31%, respectively, lower than with placebo. Individual treatment ratios for AUC((0-t)) ranged from 0.48 to 1.17, and for C(max) ranged from 0.33 to 2.19. Essentially all of the circulating active HMG-CoA reductase inhibitors and most (>94%) of the total inhibitors were accounted for by rosuvastatin. Erythromycin did not affect the proportion of circulating active or total inhibitors accounted for by circulating rosuvastatin. CONCLUSIONS: Erythromycin did not produce any increase in rosuvastatin plasma exposure. This indicates that CYP3A4 metabolism is not an important clearance mechanism for rosuvastatin, a result consistent with previous findings. The small decreases in rosuvastatin AUC((0-t)) and C(max) that occurred as a consequence of short-term treatment with erythromycin are unlikely to have relevance to long-term treatment with rosuvastatin.

Pharmacokinetics and pharmacodynamics of rosuvastatin in subjects with hepatic impairment.

OBJECTIVE: To assess the effect of chronic hepatic impairment on rosuvastatin disposition, pharmacodynamic activity and tolerability. METHODS: This was an open-label, non-randomised, parallel-group trial. Six subjects were enrolled in each of three hepatic-function strata: Child-Pugh class A (CP-A, mild impairment), Child-Pugh class B (CP-B, moderate impairment) and normal hepatic function; the latter two strata were age, weight, race, sex and smoking history matched. All subjects were given rosuvastatin 10 mg for 14 days. RESULTS: In subjects with CP-A, and in four of six subjects with CP-B, rosuvastatin steady-state AUC(0-24) and C(max) were similar to subjects with normal hepatic function (geometric mean values 60.7 ng h/ml and 6.02 ng/ml, respectively). Two of six subjects with CP-B who had the highest CP scores (i.e. the highest degrees of hepatic impairment) had the highest AUC(0-24) (128 ng h/ml and 242 ng h/ml) and C(max) (23.4 ng/ml and 96.7 ng/ml) values. Low-density lipoprotein cholesterol (LDL-C) was decreased in all strata, but the response was more variable in the CP-B group. Rosuvastatin was well tolerated, and the safety profile was similar in subjects with hepatic impairment and normal hepatic function. CONCLUSION: In most subjects with mild-to-moderate hepatic impairment, the steady-state pharmacokinetics of rosuvastatin were similar to subjects with normal hepatic function (more extensive hepatic impairment may increase systemic exposure to rosuvastatin), and most had LDL-C reductions similar to subjects with normal hepatic function.

The effect of fluconazole on the pharmacokinetics of rosuvastatin.

OBJECTIVE: To examine the effect of fluconazole, a potent inhibitor of CYP2C9 and CYP2C19, on the pharmacokinetics of rosuvastatin in healthy volunteers. Significantly increased plasma concentrations of fluvastatin have been observed following co-administration with fluconazole. METHODS: This was a randomised, double-blind, two-way crossover, placebo-controlled trial. Healthy male volunteers ( n=14) were given fluconazole 200 mg or matching placebo once daily for 11 days; rosuvastatin 80 mg was co-administered on day 8 of dosing. Plasma concentrations of rosuvastatin, N-desmethyl rosuvastatin, and active and total 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors were measured up to 96 h post-dose. RESULTS: Following co-administration with fluconazole, rosuvastatin geometric least-square mean area under the plasma concentration-time curve (AUC(0-t)) and peak plasma concentration (C(max)) were increased by 14% and 9%, respectively, compared with placebo (90% confidence intervals for the treatment ratios: 0.967 to 1.341 and 0.874 to 1.355, respectively). Individual treatment ratios for AUC(0-t) ranged from 0.59 to 2.23, and for C(max) ranged from 0.52 to 2.28. The limited data available for the N-desmethyl metabolite show that geometric mean C(max) was decreased by approximately 25% compared with placebo. Rosuvastatin accounted for essentially all of the circulating active HMG-CoA reductase inhibitors and most (>90%) of the total inhibitors. Fluconazole did not affect the proportion of circulating active or total inhibitors accounted for by circulating rosuvastatin. CONCLUSIONS: Fluconazole produced only small increases in rosuvastatin AUC(0-t) and C(max), which were not considered to be of clinical relevance. The results support previous in-vitro findings that CYP2C9 and CYP2C19 metabolism is not an important clearance mechanism for rosuvastatin.

Preclinical and clinical pharmacology of Rosuvastatin, a new 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor.

Rosuvastatin (formerly ZD4522) is a new 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor (statin) with distinct pharmacologic properties. Compared with most other statins, it is relatively hydrophilic, similar in this respect to pravastatin. Rosuvastatin has been shown to be a comparatively potent inhibitor of HMG-CoA reductase activity in a purified preparation of the catalytic domain of the human enzyme, as well as in rat and human hepatic microsomes. In rat hepatocytes, rosuvastatin was found to have significantly higher potency as an inhibitor of cholesterol synthesis than 5 other statins. Rosuvastatin was approximately 1,000-fold more potent in rat hepatocytes than in rat fibroblasts. Further studies in rat hepatocytes demonstrated that rosuvastatin is taken up into these cells by a high-affinity active uptake process. Rosuvastatin was also taken up selectively into the liver after intravenous administration in rats. Potent and prolonged HMG-CoA reductase inhibitory activity has been demonstrated after oral administration to rats and dogs. Pharmacokinetic studies in humans using oral doses of 5 to 80 mg showed that maximum plasma concentrations and areas under the concentration-time curve are approximately linear with dose. The terminal half-life is approximately 20 hours. Studies with human hepatic microsomes and human hepatocytes have suggested little or no metabolism via the cytochrome P-450 3A4 isoenzyme. On the basis of these observations, it is suggested that rosuvastatin has the potential to exert a profound effect on atherogenic lipoproteins.

[Continuous peridural analgesia vs patient - controlled intravenous analgesia for pain therapy after thoracotomy]. / Kontinuierliche Periduralanalgesie versus patientenkontrollierte intravenöse Analgesie.Schmerztherapie nach Thorakotomien.

OBJECTIVES: Continuous epidural analgesia (EA) and patient-controlled intravenous analgesia (PCA) are widely used for postoperative pain control. Studies indicate that both analgesic regimens provide good analgesia after major surgery. However, because of the following reasons it is still unclear whether one of the two modes of application is superior. First, there are conflicting data regarding the differences in pain relief and drug use between epidural and intravenous administration of opioids. Second, in many studies epidural analgesia is performed by a combination of local anaesthetics and opioids. Third, reduced morbidity was observed only in some of the studies, in which epidural analgesia provided better pain relief than systemic opioid supply. Despite these conflicting results, EA with local anaesthetics and fentanyl as well as PCA with piritramid, a highly potent mu-agonist, are routinely used in Germany. The purpose of this study was to compare these two treatments for analgesic efficacy, pulmonary function, incidence of side effects and complications in patients undergoing thoracotomy. METHODS: In this prospective randomized trial 50 patients were included. For postoperative pain control 25 patients (EA group) received thoracic epidural infusion of local anaesthetics (bupivacaine 0.125% or ropivacaine 0,2%) and fentanyl 4,5 microg/ml with a flow rate of 4-10 ml/h. 25 patients received intravenous PCA with piritramid (bolus 2, 5 mg, lock out 15 minutes, maximum of 25 mg/4 h, no background infusion). RESULTS: Analgesia at rest and while coughing, as evaluated by visual analogue scale, was significantly better in the EA group. EA also resulted in superior values of pulmonary function tests, general condition and a lower incidence of sedation and nausea. In contrast, patients with EA reported distinctly more pruritus than patients with PCA. Duration of hospital stay was shorter in the EA group, but this difference did not reach statistical significance. There was one atelectasis in the EA group. No major complications related to EA or PCA were observed. CONCLUSION: In this study EA with local anaesthetics and fentanyl provided superior postoperative pain control and a lower incidence of sedation and nausea compared to intravenous PCA with piritramid, but there was no superiority as to pulmonary complications and duration of hospital stay.

Pharmacokinetic interactions and side effects resulting from concomitant administration of lithium and divalproex sodium.

BACKGROUND: Valproic acid is added to the lithium regimens of many patients with bipolar disorder, especially those with mania refractory to lithium treatment. METHOD: We evaluated the pharmacokinetic effects and safety of coadministration of lithium and valproate in 16 healthy volunteers in this randomized, placebo-controlled, two-period (12 days each) crossover trial. Valproate or placebo was given twice daily. On Days 6-10, lithium was added. Blood samples drawn on Days 5 and 10 were analyzed for valproate by high-pressure liquid chromatography (HPLC) and for lithium by atomic absorption spectrophotometry. RESULTS: Lithium pharmacokinetics were unchanged by valproate, but valproate C(max), C(min), and AUC rose slightly during lithium coadministration. Adverse events did not change significantly. CONCLUSION: Concomitant administration of lithium and valproate appears to be safe in patients with bipolar disorder.

Effect of omeprazole on concentrations of clarithromycin in plasma and gastric tissue at steady state.

This study was conducted to determine (i) the effect of omeprazole on steady-state concentrations of clarithromycin and 14-(R)-hydroxyclarithromycin in plasma and gastric mucosa, (ii) the effect of clarithromycin on steady-state concentrations of omeprazole in plasma, and (iii) the effect of clarithromycin on the suppression of gastric acid secretion by omeprazole. Twenty healthy, Helicobacter pylori-negative male subjects completed this three-period, double-blind, randomized crossover study. In period 1, all subjects received 40 mg of omeprazole each morning for 6 days. Twenty-four-hour gastric pH monitoring took place on days -1 and 6. Pharmacokinetic sampling took place on day 6. In periods 2 and 3, subjects were randomly assigned to receive either 40 mg of omeprazole or omeprazole placebo daily for 6 days plus clarithromycin (500 mg) every 8 h for 5 days with a single 500-mg dose on day 6. Gastric tissue and mucus samples were obtained via endoscopy on day 5. Gastric pH monitoring and pharmacokinetic sampling took place on day 6. Two-week washout intervals separated the three study periods. Clarithromycin increased mean omeprazole area under the concentration-time curve from 0 to 24 h from 3.3 +/- 2.0 to 6.3 +/- 4.5 micrograms.h/ml (P < 0.05) and harmonic mean half-life from 1.2 to 1.6 h (P < 0.05) but did not significantly alter the effect of omeprazole on gastric pH. Mean clarithromycin area under the concentration-time curve from 0 to 8 h increased from 22.9 +/- 5.5 (placebo) to 26.4 +/- 5.7 micrograms.h/ml (omeprazole) (P < 0.05) when clarithromycin was administered with omeprazole. Analysis of variance revealed that mean concentrations of clarithromycin in tissue and mucus were statistically significantly higher when clarithromycin was given with omeprazole than when clarithromycin was given with placebo (P <0.001). Mean maximum observed concentrations of clarithromycin in the gastric fundus increased from 20.8 +/- 7.6 (placebo) to 24.3 +/- 6.4 micrograms/g (omeprazole), and those in the gastric mucous from 4.2 +/- 7.7 placebo to 39.3 +/- 32.8 micrograms/g (omeprazole). Similar increases were observed for the 14-(R)-hydroxyclarithromycin. These results show that omeprazole increases concentrations of clarithromycin in gastric tissue and mucus and may provide a mechanism for synergy between clarithromycin ad omeprazole that explains the excellent eradication of H. pylori seen in clinical trials.

The human immune response to KS1/4-desacetylvinblastine (LY256787) and KS1/4-desacetylvinblastine hydrazide (LY203728) in single and multiple dose clinical studies.

Monoclonal antibody (MoAb) conjugates have been used to treat a variety of malignancies. The majority of the MoAbs which have been used therapeutically are from murine sources. The infusion of these foreign proteins into humans can be expected to elicit anti-murine antibodies and may be one of the major limitations to the clinical use of murine MoAbs. In these studies, we report on the nature and specificity of the human anti-murine antibody (HAMA) response in patients given single and multiple infusions of the two Vinca alkaloid conjugates of the MoAb KS1/4, which recognizes tumor-associated antigens in a variety of adenocarcinomas. A HAMA response was induced in a majority of the patients receiving infusions of KS1/4 conjugates, regardless of the specific conjugate used or the number of infusions. The magnitude of the response did not appear to be dose related. Antibodies directed to the drug moieties of these conjugates, anti-Vinca alkaloids, were also induced in patients with HAMA responses. The magnitude of the anti-Vinca response paralleled that of the HAMA.

Relationship between steady-state plasma nizatidine concentrations and inhibition of basal and stimulated gastric acid secretion.

Steady-state plasma nizatidine concentrations were related in a linear fashion to nizatidine infusion rate. Infusion rates of 2.5, 10, and 20 mg/hr resulted in mean plasma nizatidine concentrations of 69, 247, and 575 ng/ml. Basal acid secretion was inhibited by 50% and 90% at mean plasma nizatidine concentrations of 60 and 430 ng/ml. Protein-stimulated acid secretion was inhibited by 50% and 90% at mean plasma nizatidine concentrations of 75 and 490 ng/ml. The mean pH of basal gastric secretions was 1.6 during placebo infusion and 4.6 when the mean plasma nizatidine concentration was 575 ng/ml.

Disposition of a murine monoclonal antibody vinca conjugate (KS1/4-DAVLB) in patients with adenocarcinomas.

The pharmacokinetics of a murine monoclonal antibody vinca conjugate (KS1/4-DAVLB) was investigated in 13 patients with adenocarcinomas who received single intravenous doses ranging from 40 to 250 mg/m2 and in three patients who were administered 1.5 mg/kg every 48 to 72 hours for up to 15 doses. Five patients in the single-dose study also received 100 microCi of [3H]-KS1/4-DAVLB. Overall mean values for the pharmacokinetic variables were as follows: elimination half-life, 31.5 hours; distribution volume, 4.43 L; and clearance, 0.09 L/hr. KS1/4-DAVLB demonstrated linear elimination kinetics in both the single- and multiple-dose studies. Significant concentrations of KS1/4-DAVLB were noted in a pleural effusion. Ten percent of the radioactive dose was recovered in the urine and 20% in the feces over a 5-day period. Small molecular weight vinca species were detected in the feces but not in the serum.

A pharmacokinetic profile of nizatidine in man.

In this report, the pharmacokinetic, pharmacodynamic, and hormonal effects of nizatidine are reviewed in healthy volunteers and in patients with renal or hepatic impairment. The absolute oral bioavailability of nizatidine exceeded 90%; the half-life (t1/2), plasma clearance (Clp), and volume of distribution (Vd) of iv nizatidine were 1.3 h, 461/h, and 1.21/kg, respectively. Within 16 h of dosing volunteers with nizatidine, more than 90% of the administered dose was recovered in urine as parent drug and metabolites; unchanged nizatidine accounted for 65 and 75% of the recovered substances, after oral and intravenous administration, respectively. Renal impairment decreased the elimination of nizatidine and dosage reductions are recommended for patients with creatinine clearance (Clcr) less than 50 ml/min/m2. Nizatidine suppressed gastric acid secretion produced by sham meals, protein meals, or pentagastrin; its antisecretory activity was dose and concentration dependent. Nizatidine was three times more potent than cimetidine. Nizatidine, after oral or iv administration, did not alter hormone concentrations in plasma.

Effect of time of dosing on the disposition of oral cibenzoline.

Single oral doses of cibenzoline were administered to eight healthy volunteers on two different occasions, once at 8.00 am and once at 10.00 pm, in a randomized crossover design with at least one week separating treatments. A fast was maintained for 12 hours prior to and for 2 hours after the morning dose and the subjects did not lie down for at least 12 hours after dosing. A standard dinner was eaten 3 hours prior to the evening dose, and a fast was maintained for 10 hours after dosing; the subjects laid down 2 hours after dosing for at least 6 hours. Blood was collected at specific times for 72 hours and the total volume of urine voided was collected through 72 hours. Cibenzoline concentrations in plasma and urine were measured by HPLC. Cibenzoline absorption was slower in 7 of the 8 volunteers following the evening dose relative to the morning dose. Mean +/- S.D. tmax for the evening dose was 2.6 +/- 0.5 hours compared to 1.7 +/- 0.8 for the morning dose. The corresponding mean +/- S.D. Cmax following the morning dose was 446 +/- 124 ng ml-1 compared to 402 +/- 114 ng ml-1 after the evening dose. The mean +/- S.D. AUC was 3328 +/- 1101 ng . h . ml-1 after the morning dose and 3561 +/- 1430 ng . h . ml-1 after the evening dose. The harmonic mean half-life was 7.4 hours after both treatments. These data indicated that the total amount of drug absorbed and the elimination rate constant of the drug had not varied between treatments.(ABSTRACT TRUNCATED AT 250 WORDS)

Sleep apnoea in a hypertensive population.

50 hypertensive patients and 50 normal controls were evaluated in the sleep laboratory for the presence of sleep apnoea or sleep apnoeic activity. Hypertensive patients were at high risk of sleep apnoea; 15 hypertensive patients (30%) had sleep apnoea and another 17 (34%) had sleep apnoeic activity. In contrast, none of the age-matched and sex-matched control subjects had sleep apnoea, and 24% had sleep apnoeic activity. The degree of oxygen desaturation was correlated with the duration as well as the number of apnoeic events. Presence of sleep apnoea in the patients was significantly correlated with higher blood pressure levels when they were initially seen in the clinic. Patients with the most severe sleep apnoea had the highest initial blood-pressure levels and were more refractory to treatment.

Effects of nadolol and propranolol on plasma lidocaine clearance.

Nadolol and propranolol effects on lidocaine elimination were followed in six healthy men and women. Each received three separate 30-hr infusions of lidocaine (2 mg/min): one alone, one after 3 days pretreatment with nadolol (160 mg daily), and one after 3 days pretreatment with propranolol (80 mg every 8 hr). Liver blood flow was determined by the systemic clearance of indocyanine green. Steady-state plasma lidocaine levels were increased by nadolol (2.1 +/- 0.2 to 2.7 +/- 0.3 micrograms/ml) and by propranolol (2.1 +/- 0.2 to 2.5 +/- 0.3 micrograms/ml). Lidocaine plasma clearance was decreased by nadolol (1030 +/- 81 to 850 +/- 82 ml/min) and by propranolol (1030 +/- 81 to 866 +/- 75 ml/min). Hepatic blood flow was decreased by nadolol (1275 +/- 77 to 902 +/- 102 ml/min) and propranolol (1275 +/- 77 to 957 +/- 119 ml/min). The hepatic extraction ratio for lidocaine was increased by nadolol (0.86 +/- 0.06 to 0.91 +/- 0.05) and by propranolol (0.86 +/- 0.06 to 0.90 +/- 0.06). Lidocaine intrinsic clearance was not changed by nadolol (8.19 +/- 1.87 to 9.52 +/- 2.36 l/min) or propranolol (8.19 +/- 1.87 to 9.50 +/- 3.13 l/min). Our data indicate that both nadolol and propranolol reduce lidocaine clearance by their effects on hepatic blood flow and not by inhibition of lidocaine metabolism.

Dazoxiben, a thromboxane synthetase inhibitor, in Raynaud's phenomenon.

Dazoxiben, a specific thromboxane synthetase inhibitor, was evaluated in 21 patients with Raynaud's phenomenon in a double-blind, placebo-controlled crossover experiment. Total fingertip blood flows were measured by plethysmography and capillary blood flows were measured by 133Xe disappearance rate. Subjects were studied in both a warm (28 degrees) and a cold (20 degrees) room. Arteriovenous (AV) shunt flow was estimated by subtraction of capillary flow from total flow. Ex vivo production of thromboxane B2 (TXB2) and 6-keto PGF1 alpha was determined by specific radioimmunoassay in serum from venous blood incubated for 1 hr (37 degrees). Plasma concentrations of TXB2 and 6-keto PGF1 alpha were also monitored. Dazoxiben (100 mg 4 times a day for 14 days) inhibited ex vivo TXB2 production (from 463.1 +/- 69.9 to 101.8 +/- 13.4 ng/ml/hr; (means +/- SE], enhanced ex vivo 6-keto PGF1 alpha production (from 1.38 +/- 0.05 to 3.76 +/- 0.18 ng/ml/hr), reduced plasma TXB2 concentration (from 88.1 +/- 13.9 to 38.8 +/- 5.9 pg/ml). There were no changes in plasma concentration of 6-keto PGF1 alpha. Dazoxiben did not improve total digital blood flow, capillary flow, AV shunt flow, or forearm blood flow at 28 degrees or 20 degrees. There was no subjective improvement in frequency or severity of Raynaud's attacks (assessed by patient diaries). It is concluded that dazoxiben is a potent and specific thromboxane synthetase inhibitor capable of altering arachidonic acid metabolism, but is of little or no benefit in the treatment of Raynaud's phenomenon.

Mechanism by which hydralazine increases propranolol bioavailability.

Five healthy subjects were given oral 14C-propranolol (10 microCi, 40 mg) alone and in combination with hydralazine, 25 and 50 mg. Hydralazine increased propranolol peak concentrations from 25 +/- 7 ng/ml to 61 +/- 10 and 85 +/- 11 ng/ml, reduced time to peak concentrations from 2.2 +/- 0.2 hr to 0.7 +/- 0.1 and 0.8 +/- 0.1 hr, and increased area under the propranolol concentration: time curves from 153 +/- 38 ng X ml-1 X hr to 246 +/- 64 and 324 ng X ml-1 X hr (in all cases P less than 0.05). Hydralazine did not change the fraction of the 14C-propranolol dose recovered in the urine as basic, acidic, and polar metabolites: 0.28 +/- 0.2, 0.27 +/- 0.03, and 0.44 +/- 0.03. The urinary excretion rate of radioactive metabolites of propranolol in acid, basic, and residue fractions increased in the 0 = to = 2-hr time interval after hydralazine but there was no change in the relative proportion of each metabolite fraction at any time. Similar results were obtained by HPLC. Studies with radioactive propranolol indicate that a major acid and basic metabolite remains to be defined in addition to unextracted polar metabolites. Our data indicate that hydralazine increases propranolol bioavailability by its hemodynamic actions rather than by inhibition of its metabolism.